ASIC3、TRPV1或TDAG8基因缺失會減緩關節炎誘導的熱痛覺過敏並抑制衛星膠細胞表現

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陳芊樺(Chien-Hua Chen) 查詢紙本館藏

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生命科學系

論文名稱

ASIC3、TRPV1或TDAG8基因缺失會減緩關節炎誘導的熱痛覺過敏並抑制衛星膠細胞表現
(ASIC3, TRPV1 or TDAG8 gene deficiency reduces arthritis-induced thermal hyperalgesia and inhibits satellite glia expression)

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摘要(中)

類風濕性關節炎是一種常見的自體免疫疾病，會造成滑液關節慢性發炎，傷害軟骨組織，導致關節毀損，常伴隨著長期性的疼痛。關節炎通常伴隨組織酸化。先前的研究中發現，酸敏感受體ASIC3、TRPV1和TDAG8可以減緩RA誘導的機械性痛覺過敏和關節發炎。然而，尚不清楚這些基因是否也參與在RA誘導的熱痛覺過敏中，以及它們是如何調節RA引發的疼痛。以前的研究表明，衛星膠細胞（SGCs）對於慢性疼痛的建立和維持扮演重要的角色，有希望成為控制病理性疼痛的目標。酸敏感受體可能會通過影響SGCs表現來調控疼痛。因此，我在小鼠關節處注射5μg的完全弗式佐劑，每週一次，連續注射四周，進行行為測試、關節炎程度分析及免疫組織化學螢光染色分析。連續注射CFA的小鼠會產生長期性的關節發炎、雙側熱痛覺過敏、減少DRG中的神經細胞和增加SGCs的數量。有趣的是，ASIC 3、TRPV 1和TDAG 8基因剔除小鼠從7~8週逆轉關節炎誘導的熱痛覺過敏，並抑制SGCs數量的增加。

摘要(英)

Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by chronic inflammation of the synovial joints, leading to joint damage and long-term pain. Joint inflammation is often accompanied for tissue acidosis. The previous study has found that proton-sensing receptors, ASIC3, TRPV1 and TDAG8, reduce RA-induced mechanical hyperalgesia and arthritis scores. However, it remains unclear whether these genes also affect RA-induced thermal hyperalgesia and how they regulate RA-induced pain. Previous studies have shown that satellite glial cells (SGCs) are critical to the development and maintenance of chronic pain. It is likely that proton-sensing receptors may regulate SGCs to modulate pain. To address this question, I injected 5 μg of Freund′s Complete Adjuvant (CFA) into the joints every week for four weeks and performed behavioral tests and immunohistochemical staining. Repeated CFA resulted in long-term joint inflammation, bilateral thermal hyperalgesia, DRG neuron loss, and an increase in the number of SGCs. Interestingly, ASIC 3, TRPV 1 and TDAG 8 knockout mice reversed arthritis-induced thermal hyperalgesia from 7-9 weeks, and inhibited the increase in the number of SGCs.

關鍵字(中)

★ 類風濕性關節炎
★ 衛星膠細胞

關鍵字(英)

★ Rheumatoid arthritis
★ satellite glial cells
★ ASIC3
★ TRPV1
★ TDAG8

論文目次

中文摘要 I
ABSTRACT II
致謝 III
目錄 IV
圖表目錄 VII
表目錄 VIII
第一章緒論 1
1.1 類風濕性關節炎（RHEUMATOID ARTHRITIS, RA） 2
1.2 神經膠質細胞（GLIAL CELLS） 3
1.2.1 衛星膠細胞（Satellite glial cells, SGCs）在關節炎中扮演的角色 3
1.3 酸敏感的受體和離子通道 4
1.3.1 酸敏感離子通道3（Acid-sensing ion channel, ASIC3） 4
1.3.2 辣椒素受體1（Transient receptor potential vanilloid channel 1, TRPV1） 5
1.3.3 T細胞死亡相關基因8(T cell death associated gene 8, TDAG8) 6
1.4 研究動機與目的 7
第二章材料與方法 9
2.1 實驗材料 10
2.1.1 實驗動物 10
2.1.2 實驗藥品 10
2.2 實驗方法 11
2.2.1 小鼠基因型判定 (Genotyping) 11
2.2.2 瓊酯醣膠的製備與分析 13
2.2.3 小鼠關節炎模式及關節炎程度評估 13
2.2.4 機械性痛覺行為實驗 (Von-Frey filaments test) 14
2.2.5 熱痛覺行為實驗 (Hargreavs’ test) 14
2.2.6 組織冷凍切片的製作 15
2.2.6.1 玻片前處理 15
2.2.6.2 組織包埋及冷凍組織切片 15
2.2.6.3 免疫染色 (Immunohistochemistry) 16
2.2.7 統計分析 17
第三章結果 18
3.1 重複注射完全弗氏佐劑（CFA）誘發長期關節炎與熱痛覺過敏現象 19
3.2 在野生型小鼠中長期性關節炎疼痛誘導DRG神經元數量的變化 20
3.3 在CFA誘導長期性關節炎小鼠後SGCS的表現 21
3.4 在基因ASIC3-/-小鼠關節連續注射CFA後減緩熱痛覺敏感現象 22
3.5 在基因ASIC3-/-小鼠關節連續注射CFA後減緩SGCS表現 23
3.6 在基因TRPV1-/-小鼠關節連續注射CFA後減緩熱痛覺敏感現象 24
3.7 在基因TRPV1-/-小鼠關節連續注射CFA後減緩SGCS表現 25
3.8 在基因TDAG8-/-小鼠關節連續注射CFA後減緩機械性和熱痛覺敏感現象 26
3.9 在基因TDAG8-/-小鼠關節連續注射CFA後減緩SGCS表現 27
第四章結果與討論 29
4.1 模擬類風濕性關節炎的動物模式誘發熱痛覺過敏 30
4.2 在野生型小鼠中長期性關節炎疼痛誘導DRG神經元數量的減少 31
4.3 在野生型小鼠中誘導慢性關節炎疼痛後DRG中衛星膠質細胞的表現 32
4.4 ASIC3、TRPV1及TDAG8基因剔除會減緩關節腫脹和熱痛覺敏感現象 33
4.5 剔除ASIC3、TRPV1或TDAG8基因的關節炎小鼠會抑制衛星膠質細胞的表現 35
第五章參考文獻 37
附錄 62

參考文獻

Adães, S., Almeida, L., Potes, C. S., Ferreira, A. R., Castro-Lopes, J. M., Ferreira-Gomes, J. & Neto, F. L. (2017). Glial activation in the collagenase model of nociception associated with osteoarthritis. Molecular Pain, 13: 1-12.
Adães, S., Ferreira-Gomes, J., Mendonça, M., Almeida, L., Castro-Lopes, J. M. & Neto, F. L. (2015). Injury of primary afferent neurons may contribute to osteoarthritis induced pain: an experimental study using the collagenase model in rats. Osteoarthritis and Cartilage, 23: 914-924.
Barton, N. J., McQueen, D. S., Thomson, D., Gauldie, S. D., Wilson, A. W., Salter, D. W. & Chessell, I. P. (2006). Attenuation of experimental arthritis in TRPV1R knockout mice. Experimental and Molecular Pathology, 81(2): 166-170.
Bas, B. D., Su, J., Wigerblad, G. & Svensson, C. I. (2018). Pain in rheumatoid arthritis: models and mechanisms. Pain Manag, 6(3): 265-284.
Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D. & Julius, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 389: 816-824.
Chen, C. C., Zimmer, A., Sun, W. H., Hall, J., Brownstein, M. J. & Zimmer, A. (2002). A role for ASIC3 in the modulation of high-intensity pain stimuli. PNAS, 99(13): 8992-8997.
Chen, Y. J., Huang, C. W., Lin, C. S., Chang, W. H. & Sun, W. H. (2009). Expression and function of proton-sensing G protein-coupled receptors in inflammatory pain. Molecular Pain, 5, 39.
Chen, Y., Willcockson, H. H. & Valtschanoff, J. G. (2008). Increased expression of CGRP in sensory afferents of arthritic mice - effect of genetic deletion of the vanilloid receptor TRPV1. Neuropeptides, 42(5-6): 551-556.
Choi, J. W., Lee, S. Y. & Choi, Y. (1996). Identification of a Putative G Protein-Coupled Receptor Induced during Activation-Induced Apoptosis of T Cells. Cellular Immunology 168(1): 78-84.
Christensen, B. N., Kochukov, M., McNearney, T. A., Taglialatela, G. & Westlund, K. N. (2005). Proton-sensing G protein-coupled receptor mobilizes calcium in human synovial cells. Am J Physiol Cell Physiol, 289: C601-8.
Dai, S. P., Huang, Y. H., Chang, C. J., Huang, Y. F., Hsieh, W. S., Tabata, Y., Ishii, S. & Sun, W. H. (2017). TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice. Scientific Reports 7, 41415.
Deval, E., Gasull, X., Noël, J., Salinas, M., Baron, A., Diochot, S. & Lingueglia, E. (2010). Acid-Sensing Ion Channels (ASICs): Pharmacology and implication in pain. Pharmacology & Therapeutics, 128(3): 549-558.
Elson, K., Simmons, A. & Speck, P. (2004). Satellite cell proliferation in murine sensory ganglia in response to scarification of the skin. Glia, 45: 105-109.
Feldmann, M., Brennan, F. M. & Maini, R. N. (1996). Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol., 14: 397-440.
Fernandes, E. S., Russell, F. A., Spina, D., McDougall, J. J., Graepel, R., Gentry, C., Staniland, A. A., Mountford, D. M., Keeble, J. E., Malcangio, M., Bevan, S. & Brain, S. D. (2011). A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund’s complete adjuvant-induced monarthritis. Arthritis Rheum, 63: 819-29.
Ferreira‐Gomes, J., Adães, S. Sarkander, J. & Castro‐Lopes, J. M. (2010). Phenotypic alterations of neurons that innervate osteoarthritic joints in rats. Arthritis & rheumatism, 62(12): 3677-3685.
Firestein, G. S.(2003). Evolving concepts of rheumatoid arthritis. Nature, 423: 356-361.
Gascon, E. & Moqrich, A. (2010). Heterogeneity in primary nociceptive neurons: from molecules to pathology. Arch Pharm Res, 33: 1489-1507.
Gosselin, R. D., Suter, M. R., Ji, R. R. & Decosterd, I. (2010). Glial Cells and Chronic Pain. The Neuroscientist, 16(5): 519-531.
Hanani, M. (2005). Satellite glial cells in sensory ganglia: from form to function. Brain Research Reviews, 48: 457-476.
Hanani, M. (2012). Intercellular communication in sensory ganglia by purinergic receptors and gap junctions: implications for chronic pain. Brain Research, 1487: 183-191.
Hang L. H., Yang J. P., Yin W., Wang L. N., Guo F., Ji F. H., Shao D. H., Xu Q. N., Wang X. Y. and Zuo J. L. (2012). Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats. Eur J Neurosci, 36(1), 2107-2117.
Heiberg, T., Finset, A., Uhlig, T. & Kvien, T. K. (2005). Seven year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis. Ann. Rheum. Dis., 64(2): 191-195.
Heiberg, T., Finset, A., Uhlig, T. & Kvien, T. K. (2005). Seven year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64(2), 191–195.
Hsieh, W. S., Kung, C. C., Huang, S. L., Lin, S. C. & Sun, W. H. (2017). TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis. Scientific reports, 7: 8870. DOI:10.1038/s41598-017-09200-6
Huang, C. W., Tzeng, J. N., Chen, Y. J., Tsai, W. F., Chen, C. C. and Sun, W. H. (2007). Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol. Cell. Neurosci, 36: 195-210.
Ikeuchi, M., Kolker, S. J., Burnes, L. A., Walder, R. Y. & Sluka, K. A. (2008). Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain, 137: 662–669.
Inglis, J. J., Notley, C. A., Essex, D., Wilson, A. W., Feldmann, M., Anand, P. & Williams, R. (2007). Collagen-Induced Arthritis as a Model of Hyperalgesia Functional and Cellular Analysis of the Analgesic Actions of Tumor Necrosis Factor Blockade. Arthritis & rheumatism, 56(12): 4015-4023.
Kochukov , M. Y., McNearney, T. A., Fu, Y., & Westlund , K. N. (2006). Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes. Am J Physiol Cell Physiol, 291(3): C424-432.
Nascimento, D. S. M., Castro-Lopes, J. M. & Neto, F. L. M. (2014). Satellite Glial Cells Surrounding Primary Afferent Neurons Are Activated and Proliferate during Monoarthritis in Rats: Is There a Role for ATF3? PLoS ONE, 9(9): e108152. doi:10.1371/journal.pone.0108152
Onozawa Y., Komai T. and Oda T. (2011). Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. Eur J Pharmacology, 654(3), 315–319.
Orita, S., Ishikawa, T., Miyagi, M., Ochiai, N., Inoue, G., Eguchi, Y., Kamoda, H., Arai, G., Toyone, T., Aoki, Y., Kubo, T., Takahashi, K. & Ohtori S. (2011). Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskeletal Disorders, 12:134.
Roche, P. A., Klestov, A. C. & Heim, H. M. (2003). Description of stable pain in rheumatoid arthritis: a 6 year study. The Journal of Rheumatology, 30(8): 1733-1738.
Sluka, K. A., Rasmussen, L. A., Edgar, M. M., O’Donnell, J. M., Walder, R. Y., Kolker, S. J., Boyle, D. L. & Firestein, G. S. (2013). Acid-Sensing Ion Channel 3 Deficiency Increases Inflammation but Decreases Pain Behavior in Murine Arthritis. Arthritis & rheumatism, 65(5): 1194–1202.

指導教授

孫維欣(Wei-Hsin Sun)

審核日期

2019-6-27

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